Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the sequence listings and the claims. The disclosure of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from salmonid (teleost fish) pituitaries (Kawauchi et al., 1983). In fish the 17 amino acid peptide causes aggregation of melanin within the melanophores and inhibits the release of ACTH, acting as a functional antagonist of xcex1-MSH. Mammalian MCH (19 amino acids) is highly conserved between rat, mouse, and human, exhibiting 100% amino acid identity, but its physiological roles are less clear. MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996). Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles (Rossi et al., 1997). MCH also has been reported to functionally antagonize the behavioral effects of xcex1-MSH (Miller et al., 1993; Gonzalez et al, 1996; Sanchez et al., 1997); in addition, stress has been shown to increase POMC mRNA levels while decreasing the MCH precursor preproMCH (ppMCH) mRNA levels (Presse et al., 1992). Thus MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity (Baker, 1991; Knigge et al., 1996).
Although the biological effects of MCH are believed to be mediated by specific receptors, binding sites for MCH have not been well described. A tritiated ligand ([3H]-MCH) was reported to exhibit specific binding to brain membranes but was unusable for saturation analyses, so neither affinity nor Bmax were determined (Drozdz and Eberle, 1995). Radioiodination of the tyrosine at position thirteen resulted in a ligand with dramatically reduced biological activity (see Drozdz and Eberle, 1995). In contrast, the radioiodination of the MCH analogue [Phe13, Tyr19]-MCH was successful (Drozdz et al., 1995); the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the KD=0.118 nM and the Bmax xcx9c1100 sites/cell. Importantly, the binding was not inhibited by xcex1-MSH but was weakly inhibited by rat ANF (Ki=116 nM vs. 12 nM for native MCH) (Drozdz et al., 1995). More recently specific MCH binding was reported in transformed keratinocytes (Burgaud et al., 1997) and melanoma cells (Drozdz et al., 1998), where photo-crosslinking studies suggest that the receptor is a membrane protein with an apparent molecular weight of 45-50 kDaltons, compatible with the molecular weight range of the GPCR superfamily of receptors. No radioautoradiographic studies of MCH receptor localization using this ligand have been reported as yet.
The localization and biological activities of MCH peptide suggest that the modulation of MCH receptor activity may be useful in a number of therapeutic applications. The role of MCH in feeding is the best characterized of its potential clinical uses. MCH is expressed in the lateral hypothalamus, a brain area implicated in the regulation of thirst and hunger (Grillon et al., 1997); recently orexins A and B, which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al., 1998). MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Hervxc3xa9 and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA (Bahjaoui-Bouhaddi et al., 1994). Consistent with the ability of MCH to stimulate feeding in rats (Rossi et al., 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice (Qu et al., 1996), and decreased in the hypothalami of rats treated with leptin, whose food intake and body weight gains are also decreased (Sahu, 1998). MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al., 1998). Together these data suggest a role for endogenous MCH in the regulation of energy balance and response to stress, and provide a rationale for the development of specific compounds acting at MCH receptors for use in the treatment of obesity and stress-related disorders.
In all species studied to date, a major portion of the neurons of the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called xe2x80x9cextrapyramidalxe2x80x9d motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al., 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value to consider the involvement of this MCH system in movement disorders, such as Parkinson""s disease and Huntingdon""s Chorea in which extrapyramidal circuits are known to be involved.
Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5 (5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells et al., 1992). This disease comprises neurodegenerative disorders, including an olivopontocerebellar atrophy. Furthermore, the gene for Darier""s disease, has been mapped to locus 12q23-24 (Craddock et al., 1993). Dariers"" disease is characterized by abnormalities I keratinocyte adhesion and mental illnesses in some families. In view of the functional and neuroanatomical patterns of the MCH neural system in the rat and human brains, the MCH gene may represent a good candidate for SCA2 or Darier""s disease. Interestingly, diseases with high social impact have been mapped to this locus. Indeed, the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5q12-13 using genetic linkage analysis (Melki et al., 1990; Westbrook et al., 1992). Furthermore, independent lines of evidence support the assignment of a major schizophrenia locus to chromosome 5q11.2-13.3 (Sherrington et al., 1988; Bassett et al., 1988; Gilliam et al., 1989). The above studies suggest that MCH may play a role in neurodegenerative diseases and disorders of emotion.
Additional therapeutic applications for MCH-related compounds are suggested by the observed effects of MCH in other biological systems. For example, MCH may regulate reproductive functions in male and female rats. MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al., 1996). MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al., 1996). In ovariectomized rats primed with estradiol, MCH stimulated luteinizing hormone (LH) release while anti-MCH antiserum inhibited LH release (Gonzalez et al., 1997). The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al., 1984). MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin. MCH analogues may also be useful in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH-containing neurons may participate in the neural circuitry underlying PTZ-induced seizure (Knigge and Wagner, 1997). MCH has also been observed to affect behavioral correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996). Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals.
The identification of a G-protein coupled receptor for MCH has recently been published (Chambers et al., 1999; Saito et al., 1999). These groups identified MCH as the endogenous ligand for the human orphan G-protein coupled receptor SLC-1 (Lakaye et al., 1998). The rat homologue of this receptor (now called MCH-1) was reported to be localized in regions of the rat brain associated with feeding behavior (e.g. dorsomedial and ventromedial hypothalamus) The link between MCH-1 and the effects of MCH on feeding has been strengthened by recent reports on the phenotype of MCH-1 knockout mice. Two groups have shown independently (Marsh et al, 2002; Chen et al, 2002) that the targeted disruption of the MCH-1 receptor gene (MCH-1 knockout) in mice results in animals that are hyperphagic but are lean and have decreased body mass relative to wild-type littermates. The decrease in body mass is attributed to an increase in metabolism. Each group demonstrated that the MCH-1 knockout mice are resistant to diet-induced obesity, and generally exhibit weights similar to littermates maintained on regular chow.
Finally, synthetic antagonist molecules for the MCH-1 receptor have now been described in the literature. Bednarek et al. (2002) have reported on the synthesis of high affinity peptide antagonists of MCH-1. In addition, a small molecule antagonist of MCH-1 has been described by Takekawa et al. (Takekawa et al., 2002). This compound, T-226296, exhibits high affinity for the MCH-1 receptor (xcx9c5-9 nM for rat and human MCH-1), and was shown to inhibit food intake induced by the intracerebroventricular application of MCH. These data validate the strategy of using an MCH-1 receptor antagonist to treat obesity.
Furthermore, in our own studies, we have tested MCH1 antagonists in several animal models that are well known as predictive for the efficacy of compounds in humans (Borowsky, et al., in press; unpublished data). These experiments indicate that MCH1 antagonists are useful to treat obesity, depression, anxiety, as well as urinary disorders.
As used in this invention, the term xe2x80x9cantagonistxe2x80x9d refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific, but by no means limiting, examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis. Conversely, the term xe2x80x9cagonistxe2x80x9d refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
In one embodiment of this invention, the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCH1) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vitro assays is disclosed. The in vitro receptor binding assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single cloned receptor.
Furthermore, the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa), sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCH1 receptor may be beneficial. In addition, the compounds of the present invention may be used to reduce the body mass of a subject. Furthermore, the compounds of the present invention may be used to treat urinary disorders.
This invention provides a compound having the structure: 
wherein R1 is hydrogen, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2xe2x80x94, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94COR2, xe2x80x94CO2R2, phenyl, phenoxy or straight chained or branched C1-C7 alkyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or cyclopropyl;
wherein R3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR3, xe2x80x94CO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein X is O or NH; and
wherein n is an integer from 0 to 5 inclusive.
In one embodiment, R1 is aryl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR2, xe2x80x94CO2R2, straight chained or branched C1-C7 alkyl;
wherein R3 is phenyl;
wherein A is H; and
wherein X is O.
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
In one embodiment, compound has the structure: 
In one embodiment, R1 is hydrogen, straight chained or branched C1-C7 alkyl; and wherein R3 is aryl.
In one embodiment, R2 is isopropyl; and A is hydrogen.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
The present invention also provides a compound having the structure: 
wherein R1 is aryl or heteroaryl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCH3, phenoxy, fused cyclopentanyl, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein R2 is straight-chained or branched C1-C4 alkyl or cyclopropyl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; and
wherein n is an integer from 1 to 5 inclusive.
In one embodiment, R1 is aryl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or straight chained or branched C1-C4 alkyl; and
wherein A is H.
In one embodiment, R2 is isopropyl; and
wherein n is 2.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, R1 is thienyl; and wherein A is H.
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
The invention provides a compound having the structure: 
wherein W is 
wherein each R1 is independently hydrogen, methyl or ethyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or cyclopropyl;
wherein R3 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl.
wherein each A is independently xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR3, xe2x80x94CO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein X is O, NR3, CO or may be absent; and
wherein Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl.
In one embodiment, W is 
and wherein X is O or may be absent.
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, W is 
In one embodiment, A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br.
In one embodiment, R2 is isopropyl; and A is hydrogen.
In one embodiment, the compound has the structure: 
This invention provides a compound having the structure: 
wherein W is 
wherein R1 is hydrogen, straight chained or branched C1-C7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCH3, xe2x80x94CO2CH3, xe2x80x94CF3, phenyl, straight chained or branched C1-C7 alkyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or cyclopropyl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR1, xe2x80x94CO2R1, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl or phenyl.
wherein each B is independently xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR1, xe2x80x94CO2R1, xe2x80x94OCH3, xe2x80x94OCF3, xe2x80x94CF3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR1, xe2x80x94CO2R1, xe2x80x94OCH3, xe2x80x94OCF3, xe2x80x94CF3 or straight chained or branched C1-C3 alkyl.
In one embodiment, W is 
In one embodiment, R1 is hydrogen or phenyl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl.
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
This invention provides a compound having the structure: 
wherein R1 is hydrogen, straight chained or branched C1-C7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCH3, straight chained or branched C1-C3 alkyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or cyclopropyl;
wherein R3 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCH3, or straight chained or branched C1-C3 alkyl, monofluoroalkyl or polyfluoroalkyl, or a phenyl ring fused to C6 and C7 of the indole moiety;
wherein R4 is hydrogen or aryl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, straight chained or branched C1-C3 alkyl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; and
wherein n is an integer from 2 to 4 inclusive.
In one embodiment, R3 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCF3 or xe2x80x94OCH3; and
wherein R4 is hydrogen or phenyl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl or xe2x80x94CF3.
In one embodiment, R1 is hydrogen or phenyl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCH3 or straight chained or branched C1-C3 alkyl;
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
This invention provides a compound having the structure: 
wherein each R1 is independently hydrogen or CH3;
wherein R2 is straight-chained or branched C1-C4 alkyl or cyclopropyl;
wherein R3 is benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a methylenenedioxy group or one or more xe2x80x94F or xe2x80x94Cl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein X is (CH2)2, COCH2 or CONH;
In one embodiment, R3 is phenyl optionally substituted with one or more xe2x80x94F; and
wherein A is hydrogen.
In one embodiment, X is CONH.
In one embodiment, R2 is methyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
wherein each Y is independently hydrogen or xe2x80x94F.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, R3 is benzyl optionally substituted with a methylenedioxy group or one or more xe2x80x94F or xe2x80x94Cl.
In one embodiment, the compound has the structure: 
wherein each Y is independently hydrogen or xe2x80x94F.
In one embodiment, the compound has the structure: 
In one embodiment, the compound is enantiomerically pure.
In one embodiment, the compound is diastereomerically pure.
In one embodiment, the compound is enantiomerically and diastereomerically pure.
This invention also provides a pharmaceutical composition comprising a therapeutically amount of a compound of the invention and a pharmaceutically acceptable carrier.
In one embodiment, the amount of the compound is from about 0.01 mg to about 500 mg.
In one embodiment, the amount of the compound is from about 0.1 mg to about 60 mg.
In one embodiment, the amount of the compound is from about 1 mg to about 20 mg.
In one embodiment, the pharmaceutical composition consists of a carrier which is a liquid and the composition is a solution.
In one embodiment, the pharmaceutical composition consists of a carrier which is a solid and the composition is a tablet.
In one embodiment, the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.
The invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any of the invention and a pharmaceutically acceptable carrier.
This invention also provides the method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence, or obesity comprising administering to the subject a therapeutically effective amount of the compound of the invention.
In one embodiment, the therapeutically effective amount is between about 0.03 and about 1000 mg per day.
In one embodiment, the therapeutically effective amount is between about 0.30 and about 300 mg per day.
In one embodiment, the therapeutically effective amount is between about 1.0 and about 100 mg per day.
In one embodiment, the disorder is depression.
In one embodiment, the disorder is anxiety.
In one embodiment, the disorder is obesity.
In one embodiment, the disorder is urge incontinence.
The invention provides the method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
The invention provides the method of treating a subject suffering from depression, which comprises administering to the subject an amount of a compound of any of claims of the invention effective to treat the subject""s depression.
The invention provides the method of treating a subject suffering from anxiety, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s anxiety.
The invention provides the method of alleviating urge urinary incontinence in a subject suffering from an overactive bladder, which comprises administering to the subject an amount of the compound of the invention effective to alleviate the subject""s urge urinary incontinence.
The invention provides the method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.
The invention provides the method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
The invention provides the method of treating overactive bladder in a subject, which comprises administering to the subject an amount of a compound of any of the invention effective to treat the subject""s overactive bladder.
The invention provides the method of treating a disorder in a subject, wherein the symptoms of the subject can be alleviated by treatment with an MCH1 antagonist, wherein the MCH1 antagonist is the compound of the invention.
The invention provides the method of alleviating the symptoms of a disorder in a subject, which comprises administering to the subject an amount of an MCH1 antagonist effective to alleviate the symptoms, wherein the MCH1 antagonist is the compound of the invention.
This invention provides a compound having the structure: 
wherein each V is independently phthalimide, aryl, phenoxy or heteroaryl, wherein the aryl, phenoxy or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR5; CO2R5; xe2x80x94OCOR5; xe2x80x94CON(R5)2; xe2x80x94N(R5)COR5; CN; xe2x80x94NO2; xe2x80x94N(R5)2; xe2x80x94OR5; xe2x80x94SR5; (CH2)qOR5; (CH2)qR5; (CH2)qSR5; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; aryl; phenoxy; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each W is independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; xe2x80x94OCOR3; CO2R3; xe2x80x94CON(R3)2; xe2x80x94N(R3)COR3; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; aryl; phenoxy; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein X is hydrogen or xe2x80x94OR3, provided that when X is xe2x80x94OR3 the V geminal to X cannot be phthalimide;
wherein Y is hydrogen, xe2x95x90O (carbonyl oxygen), OR3, OV, COV, xe2x95x90NNHV, xe2x95x90NNR5, NZR5, NZV, NCONV (ureas), NCONR5, NR3, carbazole, indole or phthalimide;
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OCOR3; xe2x80x94OR3; or xe2x80x94N(R3)COR3; xe2x80x94CON(R3)2;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94OCOR3; xe2x80x94CON(R3)2; xe2x80x94N(R3)COR3; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR6; CO2R3; xe2x80x94OCOR3; xe2x80x94CON(R3)2; xe2x80x94N(R3)COR3; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR6; xe2x80x94SR6; (CH2)qOR6; (CH2)qSR6; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R6 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94OCOR3; xe2x80x94CON(R3)2; xe2x80x94N(R3)COR3; aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94OCOR3; xe2x80x94CON(R3)2; xe2x80x94N(R3)COR3, CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; aryl; benzyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein Z is CO, SO2 or SO2NR6;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive; and
wherein q is an integer from 1 to 3 inclusive;
or a pharmaceutically acceptable salt thereof.
As used in the present invention, the term xe2x80x9ccycloalkylxe2x80x9d includes C3-C7 cycloalky moities which may be substituted with one or more of the following: F; CN; xe2x80x94NO2; straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl,straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl; C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C5-C7 cycloalkenyl, xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94NCOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2 or (CH2)pxe2x80x94Oxe2x80x94(CH3)mxe2x80x94CH3xe2x80x94
In the present invention, the term xe2x80x9ccycloalkenylxe2x80x9d includes C5-C7 cycloalkenyl moities which may be substituted with one or more of the following: xe2x80x94F; xe2x80x94Cl; xe2x80x94Br, xe2x80x94I; CN; xe2x80x94NO2; straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl; C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C5-C7 cycloalkenyl, xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94NCOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2 or (CH2)pxe2x80x94Oxe2x80x94(CH3)mxe2x80x94CH3.
As used in the present invention, the term xe2x80x9cheteroarylxe2x80x9d is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazzolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
In addition, the term xe2x80x9cheteroarylxe2x80x9d is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen. Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo[b]thiazolyl, imidazo[2,1-b]thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3-benzothiazolyl.
The term xe2x80x9cheteroarylxe2x80x9d also includes those chemical moieties recited above which may be substituted with one or more of the following: xe2x80x94F; xe2x80x94Cl; xe2x80x94Br, xe2x80x94I; CN; xe2x80x94NO2; straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl; C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C5-C7 cycloalkenyl, xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94NCOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2 or (CH2)pxe2x80x94Oxe2x80x94(CH3)mxe2x80x94CH3.
In still another embodiment of the above described invention, the compound has the structure: 
In a further embodiment of the instant invention, R6 is straight chained or branched C1-C7 alkyl; C3-C7 cycloalkyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; xe2x80x94OR3; xe2x80x94(CH2)qOR3; or straight chained or branched C1-C7 alkyl.
In an embodiment of the present invention, the compound has the structure: 
In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; xe2x80x94OR3; (CH2)qOR3; straight chained or branched C1-C7 alkyl; C1-C7 polyfluoroalkyl; or phenoxy.
In one embodiment of the present invention, the compound is: 
In one embodiment, the compound is: 
In one embodiment, the compound is: 
In another embodiment of the present invention, the compound has the structure: 
In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; xe2x80x94OR3; (CH2)qOR3; straight chained or branched C1-C7 alkyl; C1-C7 polyfluoroalkyl; or phenoxy.
In another embodiment of the present invention, the compound is 
In one embodiment, the compound is 
In a further embodiment of the present invention, the compound has the structure: 
In another embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; xe2x80x94OR3; xe2x80x94COR3; (CH2)qOR3; straight chained or branched C1-C7 alkyl; C1-C7 polyfluoroalkyl; aryl or phenoxy.
In yet another embodiment of the present invention, the compound is 
In one embodiment, the compound is 
In one embodiment, the compound is 
In one embodiment, the compound is 
In one embodiment, the compound is 
In one embodiment, the compound is 
In an embodiment of the present invention, the compound has the structure: 
In a further embodiment of the present invention, at least one V is phenyl optionally substituted with one or more F; Cl; Br; xe2x80x94OR3; (CH2)qOR3; straight chained or branched C1-C7 alkyl; C1-C7 polyfluoroalkyl; or phenoxy.
In yet another embodiment of the present invention, the compound is 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In an additional embodiment of the present invention, Y is hydrogen and V is phthalimide.
In an additional embodiment of the present invention, R6 is straight chained or branched C1-C7 alkyl; C3-C7 cycloalkyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; xe2x80x94OR3; xe2x80x94(CH2)qOR3; or straight chained or branched C1-C7 alkyl.
In a further embodiment of the present invention, the compound is 
In one embodiment, the compound has the structure: 
In one embodiment of the compound, at least one V is phenyl or heteroaryl optionally substituted with one or more F; Cl; Br; I; R5; xe2x80x94OR5; xe2x80x94(CH2)qOR5; xe2x80x94(CH2)qR5; straight chained or branched C1-C7 alkyl; C1-C7 monoflouroalkyl or polyflouroalkyl; or phenoxy.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment of the compound, V is phenyl which is optionally substituted with one or more F; Cl; Br; xe2x80x94OR5; xe2x80x94(CH2)qOR5; xe2x80x94(CH2)qR5; straight chained or branched C1-C7 alkyl; C1-C7 monoflouroalkyl or polyflouroalkyl; or phenoxy.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment of the compound, R5 is straight chained or branched C1-C7 alkyl; C3-C7 cycloalkyl; xe2x80x94N(R6)2; xe2x80x94OR6; xe2x80x94(OH2)qOR6; xe2x80x94CH(R6)2; xe2x80x94(CH2)qR6; or aryl benzyl or heteroaryl, wherein the aryl, benzyl or heteroaryl is optionally substituted with one or more F; Cl; I; R6; xe2x80x94N(R6)2; xe2x80x94OR6; xe2x80x94(CH2)qOR6; xe2x80x94(CH2)qR6; or straight chained or branched C1-C7 alkyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment of the compound, X is hydrogen and Y is carbazole optionally substituted with one or more F; Cl; Br; R5; xe2x80x94OR5; xe2x80x94(CH2)qOR5; xe2x80x94(CH2)qR5; straight chained or branched C1-C7 alkyl; or C1-C7 monoflouroalkyl or polyflouroalkyl; or phenoxy.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment of the compound, Y is hydrogen and V is an indole, which can be optionally substituted with one or more F; Cl; Br; R5; xe2x80x94CO2R5; xe2x80x94OR5; xe2x80x94(CH2)qOR5; xe2x80x94(CH2)qR5; straight chained or branched C1-C7 alkyl; C1-C7 monoflouroalkyl or polyflouroalkyl; or phenoxy on the 1, 2, 3, 4 , 5, 6 or 7 positions.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
The present invention provides a compound having the structure: 
wherein each X is independently O or S;
wherein q is 1 or 2;
wherein each R2 is independently H; xe2x80x94(CH2)tXR3; xe2x80x94(CH2)tC(X)N(R3)2; xe2x80x94(CH2)tCO2R3; xe2x80x94CO2R3; straight chained or branched C1-C7 alkyl optionally substituted with xe2x80x94N(R3)2; xe2x80x94CON(R3)2 or xe2x80x94N(R3)C(O)R3; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each t is independently an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R4 is aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or C1-C7 alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94COR3, xe2x80x94(CH2)nXR3, xe2x80x94(CH2)nC(X)NR3, xe2x80x94(CH2)nN(R3)C(X)R3, xe2x80x94(CH2)nCO2R3, xe2x80x94(CH2)nOCOR3, straight chained or branched C1-C7 alkyl, monofluoroalkyl OR polyfluoroalkyl or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, C1-C7 alkyl substituted with aryl, heteroaryl, or C1-C7 alkyl substituted with heteroaryl;
wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94COR3, xe2x80x94(CH2)nXR3, xe2x80x94(CH2)nC(X)NR3, xe2x80x94(CH2)nCO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where R5 and one R2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C3-C7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S;
wherein R1 is 
wherein each V is independently aryl, phenoxy or heteroaryl, wherein the aryl, phenoxy or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR5; CO2R5; xe2x80x94OCOR5; xe2x80x94CON(R5)2; xe2x80x94N(R5)COR5; CN; xe2x80x94NO2; xe2x80x94N(R5)2; xe2x80x94OR5; xe2x80x94SR5; (CH2)qOR5; (CH2)qSR5; straight chained or branched C1-C7 alkyl optionally substituted with xe2x80x94CON(R5)2, xe2x80x94N(R5)C(O)R3 or N(R3)2, straight chained or branched monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; phenoxy; or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently H; (CH2)tXR3; (CH2)tC(X)NR3; (CH2)tN(R3)C(X)R3; (CH2)tCO2R3; (CH2)tOCOR3; straight chained or branched C1-C7 alkyl optionally substituted with xe2x80x94CON(R3)2 or xe2x80x94NC(O)R3; straight chained or branched C2-C7 alkyl substituted with xe2x80x94N(R3)2; straight chained or branched C2-C7 alkenyl or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R7 is independently H; F; Cl; Br; I; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94(CH2)nXR3; xe2x80x94(CH2)nN(R3)C(O)R3; (CH2)nC(X)N(R3)2; (CH2)nCO2R3; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R3)2; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94(CH2)nXR3, xe2x80x94COR3, xe2x80x94(CH2)nC(X)N(R3)2, xe2x80x94(CH2)nCO2R3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94(CH2)nN(R3)C(O)R3; xe2x80x94N(R3)2, xe2x80x94SO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94(CH2)nXR3, xe2x80x94COR3, xe2x80x94(CH2)nC(X)N(R3)2, xe2x80x94(CH2)nCO2R3, xe2x80x94(CH2)nN(R3)C(O)R3; xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94SO2R3, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
wherein B is CO, SO2 or SO2NR6;
wherein R8 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94NR3C(O)R3; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94OCOR3; xe2x80x94CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94OCOR3; xe2x80x94NR3C(O)R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl optionally substituted with xe2x80x94CON(R3)2, xe2x80x94NR3C(O)R3 or xe2x80x94N(R3)2; straight chained or branched monofluoroalkyl, polyfluoroalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is 
or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups;
wherein each R9 is independently H; F; Cl; Br; I; xe2x80x94(CH2)mXR3; (CH2)mC(X)NR3; (CH2)mCO2R3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R10 is H; (CH2)tXR3; (CH2)tC(X)NR3; (CH2)tCO2R3; straight chained or branched C1-C7 alkyl, carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, O, or NR10;
wherein each p is independently an integer from 1 to 7 inclusive;
or a pharmaceutically acceptable salt thereof.
In a further embodiment of the present invention, the compound has the following structure: 
In an additional embodiment of the present invention, the compound has the structure: 
In an additional embodiment of the present invention, the compound has the structure: 
In one embodiment of the present invention, Z is: 
In one embodiment of the present invention, Z is: 
In an additional embodiment of the present invention, the compound has the structure: 
In one embodiment of the present invention, the compound has the structure: 
This invention provides a compound having the structure: 
wherein R1 is hydrogen, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CH3, xe2x80x94CF3, xe2x80x94COCH3, xe2x80x94CO2R2, phenyl, phenoxy or straight chained or branched C1-C7 alkyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or cyclopropyl;
wherein R3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR3, xe2x80x94CO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein X is O or NH;
wherein n is an integer from 0 to 5 inclusive;
In one embodiment, R1 is aryl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COCH3, xe2x80x94CO2R2, straight chained or branched C1-C7 alkyl;
wherein R3 is phenyl;
wherein A is H; and
wherein X is O.
In one embodiment, R2 is isopropyl.
In a preferred embodiment, X is NH, R1 is alkyl and n is 1 or 2.
In the most preferred embodiment, X is O, R1 is 3-acetyl phenyl, R2 is isopropyl, R3 is phenyl and n is 1.
In one embodiment, the compound has the structure: 
In one embodiment, compound has the structure: 
In one embodiment, R1 is hydrogen, straight chained or branched C1-C7 alkyl; and wherein R3 is aryl.
In one embodiment, R2 is isopropyl; and A is hydrogen.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
The present invention also provides a compound having the structure: 
wherein R1 is aryl or heteroaryl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCH3, phenoxy, fused cyclopentanyl, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein R2 is straight-chained or branched C1-C4 alkyl or cyclopropyl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; and
wherein n is an integer from 1 to 5 inclusive.
In one embodiment, R1 is aryl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or straight chained or branched C1-C4 alkyl; and
wherein A is H.
In one embodiment, R2 is isopropyl; and
wherein n is 2.
In a preferred embodiment, n is 2 and R2 is isopropyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, R1 is thienyl; and wherein A is H.
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
The invention provides a compound having the structure: 
wherein W is 
wherein each R1 is independently hydrogen, methyl or ethyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or
wherein R2 is straight- chained or branched C3-C4 alkyl or cyclopropyl;
wherein R3 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl.
wherein each A is independently xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR3, xe2x80x94CO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein X is O, NR3, CO or may be absent; and
wherein Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl.
In one embodiment, W is 
and wherein X is O or may be absent.
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, W is 
In one embodiment, A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br.
In one embodiment, R2 is isopropyl; and A is hydrogen.
In one embodiment, the compound has the structure: 
This invention provides a compound having the structure: 
wherein W is 
wherein R1 is hydrogen, straight chained or branched C1-C7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCH3, xe2x80x94CO2CH3, xe2x80x94CF3, phenyl, straight chained or branched C1-C7 alkyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or cyclopropyl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR1, xe2x80x94CO2R1, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl or phenyl.
wherein each B is independently xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR1, xe2x80x94CO2R1, xe2x80x94OCH3, xe2x80x94OCF3, xe2x80x94CF3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COR1, xe2x80x94CO2R1, xe2x80x94OCH3, xe2x80x94OCF3, xe2x80x94CF3 or straight chained or branched C1-C3 alkyl.
In one embodiment, W is 
In one embodiment, R1 is hydrogen or phenyl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl.
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
This invention provides a compound having the structure: 
wherein R1 is hydrogen, straight chained or branched C1-C7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCH3, straight chained or branched C1-C3 alkyl;
wherein R2 is straight-chained or branched C3-C4 alkyl or cyclopropyl;
wherein R3 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCH3, or straight chained or branched C1-C3 alkyl, monofluoroalkyl or polyfluoroalkyl, or a phenyl ring fused to C6 and C7 of the indole moiety;
wherein R4 is hydrogen or aryl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, straight chained or branched C1-C3 alkyl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; and
wherein n is an integer from 2 to 4 inclusive.
In one embodiment, R3 is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OCF3 or xe2x80x94OCH3; and
wherein R4 is hydrogen or phenyl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl or xe2x80x94CF3.
In one embodiment, R1 is hydrogen or phenyl optionally substituted with one or more xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CF3, xe2x80x94OCH3 or straight chained or branched C1-C3 alkyl;
In one embodiment, R2 is isopropyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
This invention provides a compound having the structure: 
wherein each R1 is independently hydrogen or CH3;
wherein R2 is straight-chained or branched C1-C4 alkyl or cyclopropyl;
wherein R3 is benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a methylenenedioxy group or one or more xe2x80x94F or xe2x80x94Cl;
wherein A is xe2x80x94H, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
wherein X is (CH2)2, COCH2 or CONH;
In one embodiment, R3 is phenyl optionally substituted with one or more xe2x80x94F; and
wherein A is hydrogen.
In one embodiment, X is CONH.
In one embodiment, R2 is methyl.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
wherein each Y is independently hydrogen or xe2x80x94F.
In one embodiment, the compound has the structure: 
In one embodiment, the compound has the structure: 
In one embodiment, R3 is benzyl optionally substituted with a methylenedioxy group or one or more xe2x80x94F or xe2x80x94Cl.
In one embodiment, the compound has the structure: 
wherein each Y is independently hydrogen or xe2x80x94F.
In one embodiment, the compound has the structure: 
In one embodiment, the compound is enantiomerically pure.
In one embodiment, the compound is diastereomerically pure.
In one embodiment, the compound is enantiomerically and diastereomerically pure.
This invention also provides a pharmaceutical composition comprising a therapeutically amount of a compound of the invention and a pharmaceutically acceptable carrier.
In one embodiment, the amount of the compound is from about 0.01 mg to about 500 mg.
In one embodiment, the amount of the compound is from about 0.1 mg to about 60 mg.
In one embodiment, the amount of the compound is from about 1 mg to about 20 mg.
In one embodiment, the pharmaceutical composition consists of a carrier which is a liquid and the composition is a solution.
In one embodiment, the pharmaceutical composition consists of a carrier which is a solid and the composition is a tablet.
In one embodiment, the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.
The invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any of the invention and a pharmaceutically acceptable carrier.
This invention also provides the method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence, or obesity comprising administering to the subject a therapeutically effective amount of the compound of the invention.
In one embodiment, the therapeutically effective amount is between about 0.03 and about 1000 mg per day.
In one embodiment, the therapeutically effective amount is between about 0.30 and about 300 mg per day.
In one embodiment, the therapeutically effective amount is between about 1.0 and about 100 mg per day.
In one embodiment, the disorder is depression.
In one embodiment, the disorder is anxiety.
In one embodiment, the disorder is obesity.
In one embodiment, the disorder is urge incontinence.
The invention provides the method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
The invention provides the method of treating a subject suffering from depression, which comprises administering to the subject an amount of a compound of any of claims of the invention effective to treat the subject""s depression.
The invention provides the method of treating a subject suffering from anxiety, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s anxiety.
The invention provides the method of alleviating urge urinary incontinence in a subject suffering from an overactive bladder, which comprises administering to the subject an amount of the compound of the invention effective to alleviate the subject""s urge urinary incontinence.
The invention provides the method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.
The invention provides the method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
The invention provides the method of treating overactive bladder in a subject, which comprises administering to the subject an amount of a compound of any of the invention effective to treat the subject""s overactive bladder.
The invention provides the method of treating a disorder in a subject, wherein the symptoms of the subject can be alleviated by treatment with an MCH1 antagonist, wherein the MCH1 antagonist is the compound of the invention.
The invention provides the method of alleviating the symptoms of a disorder in a subject, which comprises administering to the subject an amount of an MCH1 antagonist effective to alleviate the symptoms, wherein the MCH1 antagonist is the compound of the invention
As used in the present invention, the term xe2x80x9cheteroarylxe2x80x9d is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, carbazole, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
In addition, the term xe2x80x9cheteroarylxe2x80x9d is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen. Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo[b]thiazolyl, imidazo[2,1-b]thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3-benzothiazolyl.
The term xe2x80x9cheteroarylxe2x80x9d also includes those chemical moieties recited above which may be substituted with one or more of the following: xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, CN, xe2x80x94NO2, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl; C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C5-C7 cycloalkenyl,
The term xe2x80x9cheteroarylxe2x80x9d further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
In the present invention, the term xe2x80x9carylxe2x80x9d is phenyl or naphthyl.
The invention provides for each pure stereoisomer of any of the compounds described herein. Such stereoisomers may include enantiomers, diastereomers, or E or Z alkene or imine isomers. The invention also provides for stereoisomeric mixtures, including racemic mixtures, diastereomeric mixtures, or E/Z isomeric mixtures. Stereoisomers can be synthesized in pure form (Nxc3x3grxc3xa1di, M.; Stereoselective Synthesis, (1987) VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 B 5, (1983) Academic Press, Editor Morrison, J.) or they can be resolved by a variety of methods such as crystallization and chromatographic techniques (Jaques, J.; Collet, A.; Wilen, S.; Enantiomer, Racemates, and Resolutions, 1981, John Wiley and Sons and Asymmetric Synthesis, Vol. 2, 1983, Academic Press, Editor Morrison, J).
In addition the compounds of the present invention may be present as enantiomers, diasteriomers, isomers or two or more of the compounds may be present to form a racemic or diastereomeric mixture.
The compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably 95% pure. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The acids and bases from which these salts are prepared include but are not limited to the acids and bases listed herein. The acids include, but are not limited to, the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The acids include, but are not limited to, the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The bases include, but are not limited to ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound. Thus, in the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
The present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
This invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, the amount of the compound is from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is from about 0.01 mg to about 500 mg. In yet another embodiment, the amount of the compound is from about 0.1 mg to about 250 mg. In another embodiment, the amount of the compound is from about 0.1 mg to about 60 mg. In yet another embodiment, the amount of the compound is from about 1 mg to about 20 mg. In a further embodiment, the carrier is a liquid and the composition is a solution. In another embodiment, the carrier is a solid and the composition is a tablet. In another embodiment, the carrier is a gel and the composition is a capsule, suppository or a cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch. In yet a further embodiment, the compound may be delivered to the subject by means of a spray or inhalant.
This invention also provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
A solid carrier can include one or more substances which may also act as endogenous carriers (e.g. nutrient or micronutrient carriers), flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspenions.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
In the subject application a xe2x80x9ctherapeutically effective amountxe2x80x9d is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In a subject application, a xe2x80x9csubjectxe2x80x9d is a vertebrate, a mammal or a human.
This invention provides a method of treating a subject suffering from an abnormality wherein the abnormality is alleviated by decreasing the activity of an MCH1 receptor which comprises administering to the subject an amount of a compound of the invention which is an MCH1 receptor antagonist effective to treat the subject""s abnormality.
In separate embodiments, the abnormality is a regulation of a steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder such as Alzheimer""s disease, a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as Parkinson""s disease, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, an affective disorder such as depression and anxiety, a stress-related disorder, a fluid-balance disorder, a seizure disorder, pain, psychotic behavior such as schizophrenia, morphine tolerance, opiate addiction, migraine or a urinary disorder such as urinary incontinence.
The following description of depressive and anxiety disorders is for the purpose of illustrating the utility of the compounds of this invention. The definitions of depressive and anxiety disorders given below are those listed in Diagnostic and Statistical Manual of Mental Disorders. 4th ed. (DSM-IV; American Psychiatric Association, 1994a) or Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Revised (DSM-III-R; American Psychiatric Association, 1987). Additional information regarding these disorders can be found in this reference, as well as the others cited below, all of which are incorporated herein by reference.
Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b). Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes. A major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation (Medical Economics Company, 2002). Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
It is contemplated that the compounds of this invention will be effective in treating depression in patients who have been diagnosed with depression by administration of any of the following tests: Hamilton Depression Rating Scale (HDRS), Hamilton depressed mood item, Clinical Global Impressions (CGI)-Severity of Illness. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as the HDRS subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGI-Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes.
Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating any of all of these disorders in patients who have been diagnosed with these disorders.
Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a). The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.
It is contemplated that the compounds of this invention will be effective in treating obsessions and compulsions in patients who have been diagnosed with obsessive compulsive disorder by administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (Goodman, 1989) (for adults), National Institute of Mental Health Global OCD Scale (NIMH GOCS), CGI-Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds of this invention will be effective in preventing relapse of obsessive compulsive disorder.
Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a). A panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public.
It is contemplated that the compounds of this invention will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGI-Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these evaluations, such as a reduction in frequency or elimination of panic attacks, an improvement in the CGI-Severity of Illness scale or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds of this invention will be effective in preventing relapse of panic disorder. Social anxiety disorder, also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a). Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person""s normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
It is contemplated that the compounds of this invention will be effective in treating social anxiety disorder in patients who have been diagnosed with social anxiety disorder by administration of any of the following tests: the Liebowitz Social Anxiety Scale (LSAS), the CGI-Severity of Illness scale, the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the axis V Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II (ICD-10) World Health Organization Disability Assessment, Schedule 2 (DAS-2), the Sheehan Disability Scales, the Schneier Disability Profile, the World Health Organization Quality of Life-100 (WHOQOL-100), or other tests as described in Bobes, 1998, which is incorporated herein by reference. It is further contemplated that the compounds of the invention will be effective in inducing improvements as measured by these tests, such as the a change from baseline in the Liebowitz Social Anxiety Scale (LSAS), or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds of this invention will be effective in preventing relapse of social anxiety disorder.
Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a). It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. The diagnostic criteria for this disorder are described in further detail in DSM-IV, which is incorporated herein by reference (American Psychiatric Association, 1994a).
It is contemplated that the compounds of this invention will be effective in treating generalized anxiety disorder in patients who have been diagnosed with this disorder according to the diagnostic criteria described in DSM-IV. It is further contemplated that the compounds of the invention will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. It is also contemplated that the compounds of this invention will be effective in preventing relapse of general anxiety disorder.
Post-traumatic stress disorder (PTSD), as defined by DSM-III-R/IV (American Psychiatric Association, 1987, American Psychiatric Association, 1994a), requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include re-experiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
It is contemplated that the compounds of this invention will be effective in treating PTSD in patients who have been diagnosed with PTSD by administration of any of the following tests: Clinician-Administered PTSD Scale Part 2 (CAPS), the patient-rated Impact of Event Scale (IES) (Medical Economics Company, 2002, p. 2752). It is further contemplated that the compounds of the invention will be effective in inducing improvements in the scores of the CAPS, IES, CGI-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds of this invention will be effective in preventing relapse of PTSD.
In a preferred embodiment, the subject invention provides a method of treatment or management of the following indications: depressive disorders, anxiety disorders, eating/body weight disorders, and urinary disorders. Examples of depressive disorders are major depressive disorder or dysthymic disorder. Examples of anxiety disorders are panic disorder, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder or generalized anxiety disorder. Examples of eating/body weight disorders are obesity, weight gain, bulimia, bulimia nervosa or anorexia nervosa. Examples of urinary disorders include, but are not limited to urinary incontinence overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia.
This invention provides a method of modifying the feeding behavior of a subject, which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. This invention also provides a method of treating an eating disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the eating disorder. In an embodiment of the present invention, the eating disorder is obesity, bulimia, bulimia nervosa or anorexia nervosa.
The present invention further provides a method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject. This invention also provides a method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject. This invention also provides a method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
The present invention also provides a method of treating depression in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s depression. This invention also provides a method of treating anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s anxiety. This invention also provides a method of treating depression and anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s depression and anxiety. This invention also provides a method of treating major depressive disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s major depressive disorder. This invention also provides a method of treating dysthymic disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s dysthymic disorder. This invention also provides a method of treating obsessions and compulsions in a subject with obsessive compulsive disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s obsessions and compulsions. This invention also provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s panic disorder. This invention also provides a method of treating social anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s social anxiety disorder. This invention also provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s generalized anxiety disorder. This invention also provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s post-traumatic stress disorder.
It is contemplated that the compounds of this invention will be effective in treating obesity, including weight loss and maintenance of weight loss in patients, who have been diagnosed with obesity by the one or more of the following measurements: an increased body mass index, increased waist circumference (an indicator of intra-adominal fat), Dual Energy X-Ray Absorptiometry (DEXA) and trucal (android) fat mass. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.
It is contemplated that the compounds of this invention will be effective in treating urinary disorders in patients who have urge or mixed (with a predominance of urge) incontinence as evidenced by the number of unnecessary episodes per week, the number of unnecessary micturitions per day and a low volume voided per micturition. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.
The present invention also provides a method of treating a subject suffering from bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
The present invention provides a method of treating overactive bladder with symptoms of urge urinary incontinence, urgency and/or frequency in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s overactive bladder. This invention also provides a method of alleviating urge urinary incontinence in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject""s urge urinary incontinence. This invention further provides a method of alleviating urinary urgency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject""s urinary urgency. Additionally, this invention provides a method of alleviating urinary frequency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject""s urinary frequency.
The present invention also provides a method of treating a subject suffering from a urinary disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject""s urinary disorder. In some embodiments the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis.
The present invention provides a method of alleviating the symptoms of a disorder in a subject, which comprises administering to the subject an amount of an MCH1 antagonist effective to alleviate the symptoms, wherein the MCH1 antagonist is any of the compounds of the invention.
In an embodiment of the invention, the subject is a vertebrate, a mammal, a human or a canine. In another embodiment, the compound is administered orally. In yet another embodiment, the compound is administered in combination with food.
This invention will be better understood from the Experimental Details In a preferred embodiment, the subject invention provides a method of treatment for the following indications: depression, anxiety, eating/body weight disorders, and urinary disorders. Examples of eating/body weight disorders are obesity, bulimia, or bulimia nervosa. Examples of urinary disorders include, but are not limited to, urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia.
This invention provides a method of modifying the feeding behavior of a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
This invention also provides a method of treating an eating disorder in a subject which comprises administering to the subject an amount of a compound of this invention effective to decrease the consumption of food by the subject. In an embodiment of the present invention, the eating disorder is bulimia, obesity or bulimia nervosa. In an embodiment of the present invention, the subject is a vertebrate, a mammal, a human or a canine. In a further embodiment, the compound is administered in combination with food.
The present invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
The present invention also provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of a compound of this invention effective to treat the subject""s depression. The present invention further provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject""s anxiety. The present invention also provides a method of treating a subject suffering from depression and anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject""s depression and anxiety.
The present invention also provides a method of treating a subject suffering from major depressive disorder, dysthymic disorder, bipolar I and II disorders, schizoaffective disorder, cognitive disorders with depressed mood, personality disorders, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder, sleepwalking disorder, obsessive-compulsive disorder, panic disorder, with or without agoraphobia, posttraumatic stress disorder, social anxiety disorder, social phobia and generalized anxiety disorder.
The present invention also provides a method of treating a subject suffering from a urinary disorder which comprises administering to the subject an amount of a compound of this invention effective to treat the subject""s a urinary disorder. In some embodiments, the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
General Methods: All reactions (except for those done by parallel synthesis reaction arrays) were performed under an Argon atmosphere and the reagents, neat or in appropriate solvents, were transferred to the reaction vessel via syringe and cannula techniques. The parallel synthesis reaction arrays were performed in vials (without an inert atmosphere) using J-KEM heating shakers (Saint Louis, Mo.). Anhydrous solvents were purchased from Aldrich Chemical Company and used as received. The examples described in the patent were named using ACD/Name program (version 2.51, Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada). Unless otherwise noted, the 1H spectra were recorded at 300 and 400 MHz (QE Plus and Brxc3xcker respectively) with tetramethylsilane as internal standard. s=singlet; d=doublet; t=triplet; q=quartet; p=pentet; sext; sept; br=broad; m=multiplet. Elemental analyses were performed by Robertson Microlit Laboratories, Inc. Unless otherwise noted, mass spectra were obtained using low-resolution electrospray (ESMS) and MH+ is reported. Thin-layer chromatography (TLC) was carried out on glass plates precoated with silica gel 60 F254 (0.25 mm, EM Separations Tech.). Preparative thin-layer chromatography was carried out on glass sheets precoated with silica gel GF (2 mm, Analtech). Flash column chromatography was performed on Merck silica gel 60 (230-400 mesh). Melting points (mp) were determined in open capillary tubes on a Mel-Temp apparatus and are uncorrected.
Piperidine Side Chain Intermediates
TERT-BUTYL 4-{[(TRIFLUOROMETHYL)SULFONYL]OXY}-1,2,3,6-TETRAHYDRO-1-PYRIDINECARBOXYLATE: n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mL of dry THF at 0xc2x0 C. and stirred for 20 minutes. The reaction mixture was cooled to xe2x88x9278xc2x0 C. and tert-butyl 4-oxo-1-piperidinecarboxylate (Aldrich Chemical Company, 40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes. Tf2NPh (42.0 mmol, 15.0 g) in THF (40 mL) was added dropwise to the reaction mixture and stirred at xc2x0 C. overnight. The reaction mixture was concentrated in vacuo, re-dissolved in hexanes:EtOAc (9:1), passed through a plug of alumina and the alumina plug was washed with hexanes:EtOAc (9:1). The combined extracts were concentrated to yield 16.5 g of the desired product that was contaminated with some starting Tf2NPh.
1H NMR (400 MHz, 400 MHz, CDCl3) xcex4 5.77 (s, 1H), 4.05 (dm, 2H, J=3.0 Hz), 3.63 (t, 2H, J=5.7 Hz), 2.45 (m, 2H), 1.47 (s, 9H).
TERT-BUTYL 4-[3-(AMINO)PHENYL]-1,2,3,6-TETRAHYDRO-1-PYRIDINECARBOXYLATE: A mixture of 2 M aqueous Na2CO3 solution (4.2 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (0.500 g, 1.51 mmol), 3-aminophenylboronic acid hemisulfate (0.393 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium(0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) was heated at reflux temperature for 3 hours, under an inert atmosphere (an initial degassing of the mixture is recommended to prevent the formation of triphenylphosphine oxide). The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3xc3x97). The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatographed (silica, hexanes:EtOAc:dichloromethane (6:1:1) with 1% added isopropylamine to protect the BOC group from hydrolysis) to give 0.330 g of the desired product in 81% yield. 1H NMR (400 MHz, CDCl3) xcex4 7.12 (t, 1H, J=7.60 Hz), 6.78 (d, 1H, J=8.4 Hz), 6.69 (t, 1H, J=2.0 Hz), 6.59 (dd, 1H, J=2.2, 8.0 Hz), 6.01 (m, 1H), 4.10-4.01 (d, 2H, J=2.4 Hz), 3.61 (t, 2H, J=5.6 Hz), 2.52-2.46 (m, 2H), 1.49 (s, 9H); ESMS m/e: 275.2 (M+H)+. Anal. Calc. for C16H24N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.78; H, 7.80; N, 9.92.
TERT-BUTYL 4-[3-(AMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: A mixture of 3.10 g of tert-butyl 4-(3-aminophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (11.3 mmol) and 1.0 g of 10% Pd/C in 200 mL of ethanol was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane:methanol 95:5 with 1% isopropylamine added to protect the BOC group from hydrolysis) to give 2.63 g of the desired product (84%). 1H NMR (400 MHz, CDCl3) xcex4 7.10 (t, 1H, J=7.60 Hz), 6.62 (d, 1H, J=8.4 Hz), 6.60-6.59 (m, 2H), 4.27-4.18 (m, 2H), 3.62-3.58 (m, 2H), 2.80-2.72 (m, 2H), 2.62-2.59 (m, 1H), 1.89-1.52 (m, 4H), 1.49 (s, 9H); ESMS m/e: 277.2 (M+H)+.
TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-1,2,3,6-TETRAHYDRO-1-PYRIDINECARBOXYLATE: A mixture of saturated aqueous Na2CO3 solution (25 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and tetrakis-triphenylphosphine palladium(0) (1.15 g) and dimethoxyethane (40 mL) was heated at reflux temperature overnight. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3xc3x97). The combined organic extracts were dried and concentrated in vacuo. The crude product was chromatograghed, giving the desired product: 1H NMR (CDCl3) xcex4 8.11 (br s, 1H), 7.57 (br s, 1H), 7.41 (br d, 1H, J=7.8 Hz), 7.25 (apparent t, 1H, J=7.8 Hz), 7.08 (br d, 1H, J=7.8 Hz), 5.99 (br s, 1H), 4.03 (br m, 2H, J=2.7 Hz), 3.59 (t, 2H, J=5.7 Hz), 2.46 (m, 2H), 2.16 (s, 3H), 1.49 (s, 9H).
N1-[3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL]ACETAMIDE: A solution of 4 M HCl in dioxane (10 mL) was added to tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate (8.25 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, giving the desired product as the hydrochloride salt (2.1 g): 1H NMR (CDCl3) xcex4 7.41-7.00 (m, 4H), 6.10 (br, 1H), 3.55 (m, 2H), 3.16 (t, 2H, J=5.7 Hz), 2.44 (m, 2H), 2.19 (s, 3H).
TERT-BUTYL N-(3-BROMOPROPYL)CARBAMATE: Prepared from 3-bromopropylamine hydrobromide and BOC2O in the presence of base in dichloromethane, 9.89 mmol: 1H NMR (CDCl3) xcex4 5.07 (br, 1H), 3.31 (t, 2H, J=6.6 Hz), 3.12 (apparent br q, 2H, J=6.0 Hz), 1.92 (p, 2H, J=6.6 Hz), 1.30 (s, 9H).
TERT-BUTYL N-(3-{4-[3-(ACETYLAMINO)PHENYL]-1,2,3,6-TETRAHYDRO-1-PYRIDINYL}PROPYL)CARBAMATE: A solution of N1-[3-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]acetamide.HCl (8.24 mmol), tert-butyl N-(3-bromopropyl)carbamate and potassium carbonate (33 mmol) in dry dioxane (30 mL) was heated at reflux temperature overnight. The solids were removed by filtration, the solution was concentrated in vacuo and the product was chromatograghed, giving the desired product (110 mg). 1H NMR (CDCl3) xcex4 7.65 (s, 1H), 6.98 (s, 1H), 7.45 (d, 1H, J=7.8 Hz), 7.16 (apparent t, 1H, J=7.8 Hz), 7.10 (d, 1H, J=7.8 Hz), 6.02 (s, 1H), 5.23 (b, 1H), 3.40 (b, 2H), 3.30-1.80 (m, 10H), 2.18 (s, 3H), 1.45 (s, 9H).
N1-{3-[1-(3-AMINOPROPYL)-1,2,3,6-TETRAHYDRO-4-PYRIDINYL]PHENYL}ACETAMIDE: A 1:1 solution of TFA:CH2Cl2 (5 mL) was added to tert-butyl N-(3-{4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinyl}propyl)carbamate in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 1-3 days, saturated NaHCO3 was added until pH greater than 6, the organic layer was separated, and dried in vacuo, giving the desired product (45 mg): 1H NMR (CDCl3) xcex4 7.68 (br, 1H), 7.35 (dm, 1H, J=7.8 Hz), 7.25 (apparent t, 1H, J=7.8 Hz), 7.15 (dm, 1H, J=7.8 Hz), 6.12 (m, 1H), 3.22 (m, 2H), 3.03 (t, 2H, J=7.3 Hz), 2.78 (t, 2H, J=5.5 Hz), 2.70-2.50 (m, 4H), 2.10 (s, 3H), 1.87 (p, 2H, J=7.3 Hz).
TERT-BUTYL 4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: A mixture tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate (710 mg) and 5% Pd/C (100 mg) in EtOH (10 mL) was hydrogenated (balloon technique) at room temperature overnight. The reaction mixture was passed through a pad of Celite 545 and the pad of Celite was washed with ethanol. The combined ethanol extracts were concentrated and chromatograghed, giving the desired product (660 mg): 1H NMR (CDCl3) xcex4 7.80 (s, 1H), 7.41-7.20 (m, 3H), 6.94 (d, 1H, J=7.5 Hz), 4.21 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 2.16 (s, 3H), 1.78 (m, 2H), 1.56 (m, 2H), 1.48 (s, 9H).
N1-[3-(4-PIPERIDYL)PHENYL]ACETAMIDE: A solution of HCl in dioxane (4N, 5 mL) was added to tert-butyl 4-[3-(acetylamino)phenyl]-1-piperidinecarboxylate (660 mg) in dry dichloromethane (15 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo, giving the desired product (550 mg): mp 102-104xc2x0 C.; 1H NMR (CDCl3) xcex4 2.02 (d, J=13.2 Hz, 2H), 2.11-2.45 (m, 5H), 2.67-2.77 (m, 1H), 3.00-3.10 (m, 2H), 3.51 (d, J=10.5 Hz, 2H), 6.94 (d, J=7.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.60 (s, 1H); Anal. Calcd. For C13H19N2OCl+0.86 CH2Cl2: C, 50.78; H, 6.37; N, 8.55. Found: C, 50.80; H, 7.55; N, 7.01.
TERT-BUTYL N-(3-{4-[3-(ACETYLAMINO)PHENYL]PIPERIDINO}PROPYL)CARBAMATE: A solution of N1-[3-(4-piperidyl)phenyl]acetamide (550 mg, 0.210 mmol), tert-butyl N-(3-bromopropyl)carbamate (550 mg, 0.230 mmol), K2CO3 (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI in dioxane (20 mL) was heated at reflux temperature for 2 days. The precipitated salts were removed by filtration, concentrated in vacuo and the crude product was chromatographed, giving the desired product (340 mg): 1H NMR (CDCl3) xcex4 8.15 (s, 1H), 7.47-7.44 (m, 2H), 7.22 (t, 1H, J=7.8 Hz), 6.94 (d, 1H, J=7.8 Hz), 5.53 (b, 1H), 3.23 (b, 6H), 2.80-1.60 (m, 9H), 2.20 (s, 3H), 1.45 (s, 9H).
N1-{3-[1-(3-AMINOPROPYL)-4-PIPERIDYL]PHENYL}ACETAMIDE: TFA (1.0 mL) was added to a solution of tert-butyl N-(3-{4-[3-(acetylamino)phenyl]piperidino}propyl)carbamate (340 mg) in dry dichloromethane (10 mL) and stirred at room temperature for 5 h. A 10% aqueous solution of KOH was added to the reaction mixture until pH greater than 6 and then the dichloromethane was removed in vacuo. The aqueous layer was frozen and lyophilized to give a solid, which was extracted with methanol. Removal of the solvent gave the desired product (120 mg) as an oil: 1H NMR (CDCl3) xcex4 7.23-7.16 (apparent t, 1H, J=7.5 Hz), 6.95-6.92 (m, 1H), 3.03-2.99 (m, 2H), 2.77-2.73 (t, 2H, J=6.6 Hz), 2.50-1.60 (m, 10H), 2.13 (s, 3H).
TERT-BUTYL 4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: According to the procedure used for the synthesis of tert-butyl 4-[3-(amino)phenyl]-1,2,3,6-tetrahydro-1-pyridinecarboxylate,a mixture of 2 M aqueous Na2CO3 solution (2.2 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydro-1-pyridine-carboxylate (0.500 g, 1.51 mmol), 3-nitrophenylboronic acid (0.353 g, 2.11 mmol), lithium chloride (0.191 9, 4.50 mmol) and tetrakis-triphenylphosphine palladium(0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) afforded 0.380g of the desired product.
1H NMR (400 MHz, CDCl3) xcex4 8.23 (s, 1H), 8.11 (d, 1H, J=8.0 Hz), 7.69 (d, 1H, J=8.0 Hz), 7.51 (t, 1H, J=8.0 Hz), 6.20 (m, 1H), 4.17-4.08 (m, 2H), 3.67 (t, 2H, J=5.6 Hz), 2.61-2.52 (m, 2H), 1.50 (s, 9H); ESMS m/e: 249.1 (M+Hxe2x88x92C4H8)+.
1,2,3,6-TETRAHYDRO-4-(3-NITROPHENYL)PYRIDINE: Into a stirred solution of 5.00 g (16.0 mmol) of tert-butyl 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-carboxylate in 100 ml of 1,4-dioxane at 0xc2x0 C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3xc3x9780 mL of dichloromethane and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 2.85 g (87.5% yield) of the desired product: 1H NMR (400 MHz, CDCl3) xcex4 8.24 (s, 1H), 8.09 (d, 1H, J=8.4 Hz), 7.71 (d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 6.35-6.25 (m, 1H), 3.58 (apparent q, 2H, J=3.0 Hz), 3.14 (t, 2H, J=5.6 Hz), 2.54-2.46 (m, 2H).
TERT-BUTYL 3-(4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINYL)PROPYLCARBAMATE: A mixture of 2.80 g (14.0 mmol) of 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine, 3.60 g (15.0 mmol) of tert-butyl N-(3-bromopropyl)carbamate, 11.6 g (84.0 mmol) of K2CO3, 14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00 mmol) of tetrabutylammonium iodide in 250 mL of 1,4-dioxane was heated at reflux temperature for 14 hours. The reaction mixture was filtered and the filtrate was dried (MgSO4), concentrated in vacuo and the residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 4.35 g (85.7% yield) of the desired product: 1H NMR (400 MHz, CDCl3) xcex4 8.24 (t, 1H, J=1.9 Hz), 8.09 (dd, 1H, J=1.9, 8.0 Hz), 7.70 (apparent d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 6.23 (m, 1H), 3.29-3.18 (m, 4H), 2.75 (t, 2H, J=5.6 Hz), 2.64-2.54 (m, 4H), 1.82-1.70 (m, 2H), 1.44 (s, 9H); ESMS m/e: 362.2 (M+H)+.
3-(4-(3-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINYL)-1-PROPANAMINE: Into a stirred solution of 4.35 (12.0 mmol) of tert-butyl 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)propylcarbamate in 100 ml of 1,4-dioxane at 0xc2x0 C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling was continued for an additional 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3xc3x9780 mL of dichloromethane, the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 3.05 g (97.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) xcex4 8.24 (t, 1H, J=1.8 Hz), 8.09 (dd, 1H, J=1.8, 8.2 Hz), 7.69 (dd, 1H, J=1.8, 8.2 Hz), 7.48 (t, 1H, J=8.2 Hz), 6.24 (m, 1H), 3.21 (d, 2H, J=3.6 Hz), 2.84 (t, 2H, J=6.6 Hz), 2.75 (t, 2H, J=5.8 Hz), 2.64-2.54 (m, 4H), 1.76 (m, 2H); ESMS m/e: 262.2 (M+H)+; Anal. Calc. for C14H19N3O2 (0.06 CHCl3): C, 62.90; H, 7.16; N, 15.65. Found: C, 63.20; H, 7.16; N, 15.65.
METHYL(4S)-3-[({3-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]PROPYL}AMINO)CARBONYL]-4-(3,4-DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: A mixture of 3.02 g (6.33 mmol) 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine, 7.94 g (75.5 mmol) of K2CO3 and 1.00 mL of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate and washed 3xc3x9750 mL of 5% aqueous NaOH solution, the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) xcex4 7.80 (s, 1H), 7.22-7.02 (m, 2H), 6.95 (t, J=8.70 Hz, 1H), 6.63-6.44 (m, 4H), 4.56 (Abq, 2H), 3.62 (s, 3H), 3.33 (s, 3H), 3.32-3.20 (m, 4H), 2.96 (br s, 2H), 2.33 (t, J=7.50 Hz, 2H), 2.11-1.94 (m, 3H), 1.81-1.64 (m, 4H); ESMS m/e: 572.3 (M+H)+;
TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: Into a solution of 4.00 g (16.0 mmol) of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate and 5.60 mL (32.0 mmol) of diisopropylethylamine in 100 mL dichloromethane was slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours, washed with water, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography (silica, 50:46:3:1, hexanes:dichloromethane:methanol:isopropyl amine) to afford 2.90 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) xcex4 7.69 (s, 1H), 7.34 (d, 1H, J=7.8 Hz), 7.27 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.8 Hz), 6.04 (s, 1H), 4.05 (s, 2H), 3.62 (apparent t, 2H, J=4.9 Hz), 2.51 (m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 345.5 (M+H)+. Anal. Calc. for C20H28N2O3+0.175 CHCl3: C, 66.33; H, 7.77; N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88.
TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: A mixture of 2.90 g (8.40 mmol) of tert-butyl 4-[3-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate and 0.80 g of 10% yield Pd/C in 100 mL of ethanol was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, the filtrate was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford 2.40 g (84.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) xcex4 7.49-7.44 (m, 2H), 7.24 (t, 1H, J=7.6 Hz), 6.93 (d, 1H, J=7.6 Hz), 4.20-4.10 (m, 2H), 2.86-2.45 (m, 4H), 1.86-1.75 (m, 4H), 1.48 (s, 9H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 345.2 (M+H)+; Anal. Calc. for C20H30N2O3+0.3H2O: C, 68.27; H, 8.77; N, 7.96. Found: C, 68.25; H, 8.54; N, 7.84.
2-METHYL-N-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: Into a stirred solution of 2.20 (6.50 mmol) of tert-butyl 4-[3-(isobutyrylamino)phenyl]-1-piperidinecarboxylate in 100 ml of 1,4-dioxane at 0xc2x0 C. was bubbled HCl gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCl gas was continued for 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was neutralized by the addition of KOH pellets. The aqueous solution was extracted with 3xc3x9780 mL of dichloromethane, the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9:1, dichloromethane:methanol+1% isopropyl amine) to afford 0.700 g (46.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) xcex4 7.47 (s, 1H), 7.40 (d, 1H, J=7.8 Hz), 7.24 (t, 1H, J=7.8 Hz), 7.00 (d, 1H, J=7.8 Hz), 3.23-3.14 (m, 5H), 2.82-2.57 (m, 4H), 1.20 (d, 6H, J=6.8 Hz); ESMS m/e: 247.2 (M+H)+; The hydrochloride salt was used for the combustion analysis: Anal. Calc. for C15H22N2O+HCl+0.15 CHCl3: C, 60.51; H, 7.76; N, 9.32. Found: C, 60.57; H, 7.83; N, 8.88.
3-(4-PIPERIDINYL)ANILINE: A solution of 4 M HCl in dioxane (25 mL) was added to tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate (2.60 g, 9.00 mmol) in dichloromethane (250 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, and the residue was dissolved in water (50 mL). The mixture was nuetralized using KOH pellets and extracted with methylene chloride (3xc3x9750 mL). The combined organic extracts were dried (MgSO4), concentrated and chromatographed to give the desired product (1.03 g). 1H NMR (400 MHz, CDCl3) xcex4 7.01 (t, 1H, J=7.6 Hz), 6.62-6.54 (m, 3H), 3.16 (br d, 2H, J=10.3 Hz), 2.75 (dt, 2H, J=2.7, 12.3 Hz), 2.56 (tt, 1H, J=3.6, 12.3 Hz), 1.81 (br d, 2H, J=12.3 Hz), 1.65 (dq, 2H, J=4.0, 12.3 Hz); ESMS m/e: 177.2 (M+H)+.
TERT-BUTYL 4-(4-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINECARBOXYLATE: To a 25-mL RB flask, equipped with a condensor, was added tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate (1.0 g), 4-nitrophenylboronic acid (0.71 g), sodium carbonate (0.430 mL of 2M solution), lithium chloride (0.382 g), tetrakis(triphenylphosphine)-palladium(0) (0.173 g) and ethylene glycol dimethyl ether (10 mL). The reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100xc2x0 C. for 3 hrs. After cooling to room temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3xc3x9720 mL) and the combined organic extracts were washed with sat NH4Cl (20 mL) and brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (6:1=hexane:ethyl acetate with 1% NH3) to afford the product (0.55 g, 59.9%) as a yellow oil. The compound is not stable at room temperature and should be used as promptly as practical: 1H NMR (400 MHz, CDCl3) xcex4 8.20 (d, 2H, J=8.6 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.24 (m, 1H), 4.13 (m, 2H), 3.67 (apparent t, 2H, J=5.5 Hz), 2.55 (m, 2H), 1.49 (s, 9H).
4-(4-NITROPHENYL)-1,2,3,6-TETRAHYDROPYRIDINE: 4-(4-Nitrophenyl)-1,2,3,6-tetrahydropyridine was prepared by a similar procedure to that used for the preparation of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide using HCl gas and tert-Butyl 4-(4-Nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (130 mg) in dioxane (5.0 mL) at room temperature. The reaction mixture was concentrated in vacuo to give the crude product (69.8 mg) which used in the next reaction without further purification.
Oxazolidinone Intermediates:
AMINO-(3,4-DIFLUOROPHENYL)-ACETONITRILE: Through a solution of 3,4-difluorobenzaldehyde (25.0 g, 0.176 mol) in MeOH (500 mL) in a round bottom flask, was bubbled ammonia gas for two hours at room temperature. The flask was then cooled to 0xc2x0 C. and trimethylsilyl cyanide was then added slowly. The reaction mixture was stirred for 2 h, at which time TLC analysis indicated that the reaction was complete (Rf=0.35, 3:2 hexane/EtOAc). The solvent was removed in vacuo and the residue was subjected to flash column chromatography on silica gel to obtain the desired product, which was used in the next step without purification.
AMINO-(3,4-DIFLUOROPHENYL)-ACETIC ACID METHYL ESTER: Into a well-stirred solution of amino-(3,4-difluorophenyl)-acetonitrile (22.0 g, 0.130 mol), a solution of HCl in MeOH (200 mL) was added at room temperature. The resulting yellow solution was stirred at room temperature for 10 h and was heated at reflux temperature for 1.5 h. After cooling, the solvent was removed in vacuo and the resulting yellow solid was dissolved in water (200 mL). The aqueous solution was then carefully basified with 20% NaOH solution to pH 9. The aqueous layer was extracted with CH2Cl2 (3xc3x97100 mL). The organic layer was separated and dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain the desired product which was used in the next step without purification.
2-AMINO-2-(3,4-DIFLUOROPHENYL)-ETHANOL: Into a well-stirred suspension of LiAlH4 (4.7 g, 0.125 mol) in THF (120 mL) in a 3-necked round bottom flask fitted with a condenser and a dropping funnel, was added a solution of amino-(3,4-difluorophenyl)-acetic acid methyl ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise at 0xc2x0 C. The resulting greenish brown suspension was heated at reflux temperature for 2 h. The reaction mixture was cooled to 0xc2x0 C. and then carefully quenched sequentially with 5 mL of water, 5 mL of 3N NaOH followed by 15 mL of water. The resulting suspension was filtered through a fritted glass funnel. To the filter cake was added 100 mL Et2O and the suspension was heated at reflux temperature for 20 min. The suspension was filtered and the combined filtrates were dried over MgSO4, filtered and the solvent was removed in vacuo. 2-Amino-2-(3,4-difluorophenyl)-ethanol was obtained as a yellow glassy syrup which was used in the next step without further purification.
[1-(3,4-DIFLUOROPHENYL)-2-HYDROXY-ETHYL]-CARBAMIC ACID-TERT-BUTYL ESTER: Into a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (8.6 g, 49.7 mmol) in CHCl3 (150 mL) at 0xc2x0 C. was added a solution of di-tert-butyl dicarbonate (11.4 g, 52.0 mmol) in CHCl3 (50 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester as a white solid (10.0 g, 74% yield).
(+)-4-(3,4-DIFLUOROPHENYL)-OXAZOLIDIN-2-ONE: Into a well-stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) at R.T. was added a solution of [1-(3,5-difluorophenyl)-2-hydroxy- ethyl]-carbamic acid-tert-butyl ester (5.0 g, 18.3 mmol) in THF (20 mL) via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of Et2O, washed with brine, filtered and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf=0.15, 3:2 hexane-EtOAc) to obtain 4-(3,5-difluorophenyl)-oxazolidin-2-one as a white flaky solid (2.8 g, 77% yield). M.P. 81-83xc2x0 C.; 1H NMR (300 MHz, CDCl3) xcex4 7.23-7.03 (m, 3H), 6.08 (br s, 1H), 4.94 (dd, J=6.6 Hz, J=8.7 Hz, 1H), 4.73 (t, J=8.7 Hz, 1H), 4.13 (dd, J=6.6 Hz, J=8.7 Hz, 1H). The enantiomers were separated by HPLC on a Chiralcel OD (20xc3x97250 mm) column using 80% hexane/20% isopropyl alcohol as the eluting system at 12.0 mL/min (U.V. 254 nm). The retention times for the two isomers were 16.19 min and 20.08 min respectively.
4-NITROPHENYL(4S)-4-(3,4-DIFLUOROPHENYL)-2-OXO-1,3-OXAZOLIDINE-3-CARBOXYLATE: Into a suspension of NaH (0.14 g, 5.30 mmol) in 20 mL of anhydrous THF under argon, a solution of (+)-4-(3,4-difluorophenyl)-oxazolidin-2-one (0.88 g, 4.42 mmol) in THF was added dropwise (dropping funnel). The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (1.11 g, 5.30 mmol) in 25 mL of THF and cooled at xe2x88x9278xc2x0 C. over a period of 15 min. The stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2Cl2 (Rf=0.4, CH2Cl2) to obtain the desired product as a white solid (1.55 g, 86% yield). Similarly, following the above procedure, 4-(3,5-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester and 4-(3,4,5-trifluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester were obtained by substituting 3,4-diflourobenzaldehyde in the first step with 3,5-diflourobenzaldehyde or 3,4,5-triflourobenzaldehyde, respectively. The oxazolidinone enantiomers were resolved by HPLC on a Chiralcel OD column (as in the previous example) and the 4-nitro-phenyl carbamates were prepared using 4-nitrophenyl chloroformate.
4-NITROPHENYL(4S)-4-(3,5-DIFLUOROPHENYL)-2-OXO-1,3-OXAZOLIDINE-3-CARBOXYLATE: Following the procedure for the synthesis of 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,5-diflourobenzaldehyde yielded the desired product. 1H NMR (400 MHz, CDCl3) xcex4 8.26 (d, 2H, J=9.3 Hz), 7.33-6.81 (m, 5H), 5.41 (dd, 1H, J=4.1, 8.7 Hz), 4.81 (t, 1H, J=9.3 Hz), 4.33 (dd, 1H, J=4.1, 9.3 Hz); Anal. Calc. for C16H10F2N2O6+0.2EtOAc: C, 52.84; H, 3.06; N, 7.34. Found: C, 53.26; H, 2.83; N, 7.73.
4-NITROPHENYL(4S)-2-OXO-4-(3,4,5-TRIFLUOROPHENYL)-1,3-OXAZOLIDINE-3-CARBOXYLATE: Following the procedure for the synthesis of 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,4,5-triflourobenzaldehyde yielded the desired product. 1H NMR (400 MHz, CDCl3) xcex4 8.27 (d, 2H, J=9.0 Hz), 7.31 (d, 2H, J=9.0 Hz), 7.11-7.02 (m, 2H), 5.37 (dd, 1H, J=4.1, 9.0 Hz), 4.81 (apparent t, 1H, J=9.0 Hz), 4.33 (dd, 1H, J=4.1, 9.0 Hz); Anal. Calc. for C16H9F3N2O6: C, 50.27; H, 2.37; N, 7.33. Found: C, 50.56; H, 2.50; N, 7.49.
1-(3,4-DIFLUOROPHENYL)-2-METHYL-2-HYDROXYPROPYLAMINE: Into a well-stirred solution of methyl 2-amino-2-(3,4-difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrous ether (200 mL) at 0xc2x0 C. a solution of methylmagnesium bromide (3 M, 87 mL, 261 mmol) in ether was added over 10 minutes. The reaction mixture was stirred at 0xc2x0 C. for 2.5 h and allowed to warm to room temperature. After 12 h, the reaction mixture was carefully poured onto a mixture of ice (300 g) and saturated aqueous ammonium chloride (50 9). The ether layer was separated and the aqueous layer was extracted with more ether (4xc3x97200 mL). The combined extracts were dried with magnesium sulfate and the solvent evaporated. The crude product was purified by column chromatography on silica gel using chloroform/methanol/2M ammonia in methanol (1000:20:10, 1000:40:20, 1000:80:40) as the eluent to give the product as an oil (6.5 g, 62% yield) which was used in the next step without further purification.
4-(3,4-DIFLUOROPHENYL)-5,5-DIMETHYL-2-OXO-OXAZOLIDINE: A mixture of 1-(3,4-difluorophenyl)-2-methyl-2-hydroxypropylamine (3.00 g, 14.9 mmol) and carbonyldiimidazole (2.418 g, 14.9 mmol) in dichloromethane (150 mL) was heated at reflux temperature for 36 h and the solvent evaporated. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) to give the product as a viscous oil which solidified on standing (1.80 g, 50% yield). The product was used in the next step without further characterization.
4-NITROPHENYL 4-(3,4-DIFLUOROPHENYL)-5,5-DIMETHYL-2-OXO-1,3-OXAZOLIDINE-3-CARBOXYLATE: Into a stirred suspension of sodium hydride (60% suspension in paraffin 203 mg, 1.4 eq.) in THF (20 mL) at 0xc2x0 C., a solution of 4-(3,4-difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine (870 mg, 3.622 mmol) in THF (5 mL) was added followed by stirring for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (950 mg, 4.71 mmol) in THF (20 mL) at xe2x88x9278xc2x0 C. under argon and the stirring was continued for 2 h. It was slowly warmed to room temperature and after 4 h the solvent was evaporated. The residue was mixed with dichloromethane (150 mL), washed with 0.05 N sodium hydroxide (3xc3x9710 mL), and dried (sodium sulfate). The solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) as the eluent to give the product as a white powder (860 mg, 59% yield).
1H NMR (400 MHz, CDCl3) xcex4 8.24 (d, 2H, J=9 Hz), 7.29-6.97 (m, 5H), 5.04 (s, 1H), 1.09 (s, 6H); Anal. Calc. for C18H14F2N2O6+0.2% H2O: C, 54.61; H, 3.67; N, 7.08. Found: C, 54.89; H, 3.59; N, 7.41.
(3,4-DIFLOUROPHENYL)-N(DIPHENYLMETHYLENE)METHANAMINE: Into a solution of 3,4-difluorobenzylamine (9.8 g, 69 mmol) and benzophenone (13.0 g, 71.0 mmol) in toluene (200 mL) was added a catalytic amount of BF3.OEt2 and the resulting solution was heated at reflux temperature for 12 h. The reaction mixture was concentrated in vacuo, yielding an oil (21 g,  greater than 95%), which was characterized by NMR analysis and subjected to the following reaction without any further purification. 1H NMR (CDCl3) xcex4 4.57 (s, 2H), 7.80-6.80 (m, 13H).
1-(3,4-DIFLOUROPHENYL)-1-[(DIPHENYLMETHYLENE)AMINO]PROPAN-2-OL: Into a solution of the benzhydrylindene-(3,4-difluoro-benzyl)-amine (21 g, 69 mmol) in 250 ml of dry THF was added tert-butyllithium (1.7 M, 60 ml) dropwise and the resulting solution was stirred at xe2x88x9278xc2x0 C. for 0.5 h. To the solution was added acetaldehyde (10 ml, 180 mmol) in 100 ml of THF and the solution was stirred at xe2x88x9278xc2x0 C. for 2 h and 25xc2x0 C. for 1 h. The reaction mixture was quenched by addition of brine. The reaction mixture was diluted with 500 ml of Et2O and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to give an oil, which was taken to the next step without any further purification. 1H NMR (CDCl3) xcex4 1.04 (d, 3H), 2.77 (broad s. 1H), 4.08 (m, 1H), 4.15 (d, 1H), 7.80-6.80 (m, 13H).
1-AMINO-1-(3,4-DIFLUORO-PHENYL)-PROPAN-2-OL: A solution of crude product from the previous procedure and MeONH2.HCl (10 g, 120 mmol) was diluted in 200 ml of MeOH and stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding an oily residue, which was re-dissolved in 200 ml of EtOAc and washed with brine. The organic layer was concentrated in vacuo to produce an oily mixture, which was subjected to column chromatography [5% NH3 (2.0 M in MeOH) in CHCl3] to yield the desired product (8.8 g, 68% yield from 3,4-difluorobenzylamine) as a mixture of diastereomers. 1H NMR (CDCl3) (xcx9c4:1 mixture of the diastereomers) xcex4 1.02 (d, J=6.0 Hz, 3H), 1.04 (d, J=6.3 Hz, 3H), 2.10 (br, 6H), 3.56-3.69 (m, 2H), 3.88-3.92 (m, 2H), 7.02-7.17 (m, 6H).
[1-(3,4-DIFLUOROPHENYL)-2-HYDROXY-PROPYL]-CARBAMIC ACID-TERT-BUTYL ESTER: Into a solution of 1-amino-1-(3,4-difluorophenyl)-propan-2-ol (13.1 g, 70.1 mmol) in CHCl3 (150 mL) at 0xc2x0 C. was added a solution of di-tert-butyl dicarbonate (19.3 g, 87.6 mmol) in CHCl3 (50 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [1-(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester as a viscous oil (18.4 g, 91% yield). 1H NMR (CDCl3) (xcx9c4:1 mixture of the diastereomers) xcex4 1.05 (d, J=6.6 Hz, 3H), 1.25 (d, J=6.0 Hz, 3H), 1.41 (br, 20H), 3.92-4.19 (br, 2H), 4.45-4.60 (m, 2H), 5.41-5.49 (br, 2H), 7.02-7.17 (m, 6H).
4-(3,4-DIFLUOROPHENYL)-5-METHYL-OXAZOLIDIN-2-ONE: Into a well-stirred solution of [1-(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) in THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. When the reaction was carried out on a larger ( greater than 5 g) scale, 1.0 equivalent of KH and 1.5 eq. of NaH was used as the base. The resulting suspension was stirred for 3 h at about 35xc2x0 C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.16 g, Rf=0.6, 3:1 hexane-EtOAc; second isomer: 0.18 g, Rf=0.5, 3:1 hexane-EtOAc). NOE experiments suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups. The 1H NMR spectrum for the trans diastereomer is as follows. 1H NMR (CDCl3) xcex4 1.49 (d, J=6.0 Hz, 3H), 4.37 (dq, J=6.0 Hz, J=7.2 Hz, 1H), 4.45 (d, J=7.2 Hz, 1H), 6.63 (br s, 1H), 7.08-7.28 (m, 3H).
The 1H NMR spectrum for the cis diastereomer is as follows. 1H NMR (CDCl3) xcex4 0.96 (d, J=6.6 Hz, 3H), 4.91 (d, J=8.1 Hz, 1H), 4.99 (dq, J=6.6 Hz, J=8.1 Hz, 1H), 6.63 (br s, 1H), 7.08-7.28 (m, 3H).
4-(3,4-DIFLUOROPHENYL)-5-METHYL-2-OXO-OXAZOLIDINE-3-CARBOXYLIC ACID-4-NITRO-PHENYL ESTER: Into a solution of one of the two diastereomers of 4-(3,4-difluorophenyl)-5-methyl-oxazolidin-2-one (0.97 g, 4.55 mmol) in 60 mL THF was added a solution of n-butyllithium in hexane (3.06 mmol, 4.9 mmol) dropwise via a syringe under argon atmosphere at xe2x88x9278xc2x0 C. The resulting yellow solution was stirred at xe2x88x9278xc2x0 C. for 40 min. This solution was then added dropwise via a cannula into another round bottom flask containing a solution of 4-nitrophenylchloroformate (1.03 g, 5.1 mmol) in 60 mL of THF, cooled at xe2x88x9278xc2x00 C., over a period of 15 min. After five minutes, the flask was removed from the cooling bath and stirring was continued for 1 h. The reaction mixture was quenched by adding ice and it was extracted with EtOAc. The organic extracts were washed with brine and the organic layer was dried over Na2SO4. The solvent was removed after filtration and the residue was purified by column chromatography on silica gel with 1:1 hexane/CH2Cl2 followed by CH2Cl2 to give the desired product.
The relative configurations of the cis and trans isomers were assigned on the basis of 1H NMR analysis of the respective p-nitrophenyloxycarbonyl derivatives. For the trans isomer, an NOE was observed between the protons of the C-5 methyl group and the proton at C-4. No NOE was observed between the protons at the C-4 and C-5 positions of this isomer, which was thus assigned trans stereochemistry. For the cis isomer, no NOE was observed between the protons of the C-5 methyl group and the proton at C-4. However, a NOE was observed between the protons at the C-4 and C-5 positions, leading us to assign this isomer cis stereochemistry. The vicinal coupling constants of the C-4 protons of cis (J=7.8 Hz) and trans (J=5.1 Hz) are also consistent with the values reported for similar oxazolidinones, and were thus helpful in making the stereochemical assignments (Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995, 181).
Enantiomers of the diastereomers were separated by HPLC by using a Chiralcel OD column (20xc3x97250 mm) with 80% hexane/20% isopropyl alcohol/0.1% diethylamine as the eluting system (12 mL/min) under isocratic conditions (U.V. 254 nm).
In order to assign the absolute configurations at the stereogenic centers of the oxazolidinone rings, a new synthetic route was designed which employed an enantiomerically pure substrate derived from the chiral pool. Commercially available (S)-(+)-methyl lactate was converted into its pyrrolidine amide according to the method of Martin et al (Martin, R.; Pascual, O.; Romea, P.; Rovira, R.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1997, 38, 1633). Following the protection of the hydroxy group of (2S)-1-oxo-1-(1-pyrrolidinyl)-2-propanol to a TBDMS group, treatment of tert-butyl(dimethyl)silyl(1S)-1-methyl-2-oxo-2-(1-pyrrolidinyl)ethyl ether with 3,4-difluorophenyllithium yielded (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-difluorophenyl)-1-propanone as the sole product, which was then converted to (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-difluorophenyl)-1-propanone oxime. Reduction of the (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-difluorophenyl)-1-propanone oxime with LiAlH4, N-acylation, and base induced cyclization provided oxazolidinone diastereomers, which were separated by flash column chromatography. The enantiomeric purity of these isomers was confirmed by chiral HPLC analysis and their relative configurations were assigned by comparison of their 1H NMR spectra with those of the racemic isomers. As the absolute configuration at C-5 of the lactic acid derived oxazolidinone described above is (S), the C-4 center in trans compounds also has the (S) configuration. Accordingly, the absolute configurations for the stereogenic centers in the cis compounds are assigned accordingly (4R,5S).
4-NITROPHENYL(4S,5R)-4-(3,4-DIFLUOROPHENYL)-5-METHYL-2-OXO-1,3-OXAZOLIDINE-3-CARBOXYLATE: 1H NMR (400 MHz, CDCl3) xcex4 8.25 (d, 2H, J=8.8 Hz), 7.30-6.99 (m, 5H), 5.35 (d, 1H, J=7.7 Hz), 5.07 (apparent quintet, 1H), 1.17 (d, 3H, J=6.5 Hz); Anal. Calc. for C17H12F2N2O6+0.5H2O: C, 52.72; H, 3.38; N, 7.23. Found: C, 53.09; H, 3.19; N, 7.50.
(+)-2-AMINO-3-(3,4-DIFLUORO)-PHENYL-PROPAN-1-OL: (+)-3,4-difluorophenyl alanine (1.0 g, 5.0 mmol) was added in small portions to a stirring suspension of LiAlH4 (0.480 g, 12.5 mmol) in THF (30 mL) at 0xc2x0 C. The resulting gray suspension was then heated at reflux for 2 h. The reaction mixture was cooled to 0xc2x0 C. and then carefully quenched sequentially with water (0.5 mL), 3 N NaOH (0.5 mL), and water (1.50 mL). The resulting suspension was filtered through a fritted glass funnel. Ether (50 mL) was added to the filter cake and the suspension was heated at reflux temperature for 20 min. The suspension was filtered and was combined with the previous filtrate. The combined organics were dried over MgSO4, filtered and the solvent was removed in vacuo. 2-Amino-3-(3,4-difluoro)-phenyl-propan-1-ol was obtained as a white solid (0.500 g, 100%) which was used in the next step without further purification.
(+)-[1-(3,4-DIFLUOROBENZYL)-2-HYDROXY-ETHYL]-CARBAMIC ACID-TERT-BUTYL ESTER: A solution of di-tert-butyl dicarbonate (0.640 g, 2.90 mmol) in CHCl3 (10 mL) was added in one portion to a solution of (+)-2-amino-3-(3,4-difluoro)-phenyl-propan-1-ol (0.500 g, 2.62 mmol) in CHCl3 (20 mL) at 0xc2x0 C. and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was chromatographed (2:1 hexane-EtOAc, followed by EtOAc), giving (+)-[1-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester as a white solid (0.640 g, 99%).
(+)-4-(3,4-DIFLUORO-BENZYL)-OXAZOLIDIN-2-ONE: A solution of (+)-[1-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (1.00 g, 4.00 mmol) in THF (10 mL) was added via a dropping funnel to a stirring suspension of 95% NaH (0.12 g, 5.0 mmol) in THF (20 mL) at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with water (10 mL). The biphasic mixture was extracted with Et2O (50 mL), washed with brine, filtered and the solvent was removed in vacuo. The resulting gummy residue was purified by column chromatography (Rf=0.25, 3:2 hexane-EtOAc), to give the desired product as a white solid (0.320 g, 76%).
(+)-4-(3,4-DIFLUORO-BENZYL)-OXAZOLIDIN-2-ONE-3-CARBOXYLIC ACID-4-NITRO-PHENYL ESTER: A solution of (+)-4-(3,4-difluoro-benzyl)-oxazolidin-2-one (0.210 g, 1.0 mmol) in THF (10 mL) was added dropwise via a dropping funnel to a stirring suspension of NaH (30.0 mg, 1.30 mmol) in anhydrous THF (10 mL) under argon. The resulting suspension was stirred at room temperature for 30 min. This suspension was then added dropwise via cannula to a solution of 4-nitrophenylchloroformate (0.300 g, 1.50 mmol) in THF (20 mL) at xe2x88x9278xc2x0 C. over 15 min. Stirring was continued for 2 h after which the solvent was removed and the residue was purified by column chromatography (1:1 hexane/CH2Cl2, followed by CH2Cl2; Rf=0.4, CH2Cl2), to give the desired product as a yellow solid (0.350 g, 82%).
Similarly, following the above procedure, 4-nitrophenyl 4-(4-fluorobenzyl)-2-oxo-1,3-oxazolidine-3-carboxylate was obtained by substituting (+)-3,4-diflourophenyl alanine with p-fluorophenyl alanine:
4-NITROPHENYL 4-(4-FLUOROBENZYL)-2-OXO-1,3-OXAZOLIDINE-3-CARBOXYLATE: 1H NMR (400 MHz, CDCl3) xcex4 8.32 (d, 2H, J=9.3 Hz), 7.42 (d, 2H, J=8.9 Hz), 7.24-6.99 (m, 4H), 4.69-4.59 (m, 1H), 4.35 (t, 1H, J=8.6 Hz), 4.23 (dd, 1H, J=2.7, 9.3 Hz), 3.37 (dd, 1H, J=3.8, 13.6 Hz), 2.94 (dd, 1H, J=9.3, 13.6 Hz); Anal. Calc. for C17H13FN2O6: C, 56.67; H, 3.64; N, 7.77. Found: C, 56.94; H, 3.76; N, 7.71.
2-[6-(4-PHENYL-1-PIPERIDINYL)HEXYL]-1H-ISOINDOLE-1,3(2H)-DIONE: To the 500 ml RB-flask was added 4-phenylpiperidine hydrochloride (5 g, 25 mmol), N-(6-bromohexyl)phthalimide (15.5 g, 50 mmol), N,N-diisopropylethylamine (21.8 ml, 125 mmol), tetrabutylammonium iodide (0.2 g), and dioxane (250 ml) at room temperature. The reaction mixture was stirred at 100xc2x0 C. for 72 h. The solvent was removed in vacuo and the crude product was purified by flash chromatography (98:2=Chloroform:2N ammonia in methanol) to afford 7.67 g of the desired product (77% yield): 1H NMR (400 MHz, CDCl3) xcex4 7.78-7.79 (m, 2H), 7.74-7.65 (m, 2H), 7.32-7.14 (m, 5H), 3.69 (t, 2H, J=7.35 Hz), 3.06 (d, 2H, J=11.0 Hz), 2.49 (quintet, 1H, J=7.6 Hz), 2.36 (t, 2H, J=7.6 Hz), 2.02 (t, 2H, J=12.5 Hz), 1.82 (br s, 4H), 1.69 (t, 2H, J=6.3 Hz), 1.54 (br s, 2H), 1.37 (br s, 4H); ESMS m/e: 391.3 (M+H)+; Anal. Calc. for C25H30N2O2+0.2H2O: C, 76.19; H, 7.77; N, 7.11. Found: C, 76.14; H, 7.38; N, 7.13.
METHOD I. General procedure for the Preparation of the substituted 4-[4-(3-aminophenyl)-1-piperidinyl]-1-(phenyl)-1-butanones: A mixture of 4-(3-aminophenyl)piperidine (2.0 mmol), 2.4 mmol of the appropriate substituted phenyl butyryl chloride (e.g. 4-chloro-4xe2x80x2-phenoxybutyrophenone, 4-chloro-3xe2x80x2,4xe2x80x2-dimethylbutyrophenone, 4-chloro-4xe2x80x2-chlorobutyrophenone, xcex3-chlorobutyrophenone, 4-chloro-3xe2x80x2,4xe2x80x2-dimethoxybutyrophenone), 3.0 mmol of K2CO3, and 10 mg of 18-crown-6 in 5 mL of toluene were heated at 110xc2x0 C. for 2.5 days. The reaction mixture was concentrated and chromatographed on silica (5% methanol in dichloromethane) to give the desired compound:
4-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]-1-(4-PHENOXYPHENYL)-1-BUTANONE: Using Method I, the desired product was obtained. 305 mg; ESMS m/e: 415.4 (M+H)+.
4-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]-1-(3,4-DIMETHYLPHENYL)-1-BUTANONE: Using Method I, the desired product was obtained. 320 mg; ESMS m/e: 351.3 (M+H)+.
4-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]-1-(4-CHLOROPHENYL)-1-BUTANONE: Using Method I, the desired product was obtained. 500 mg; Anal. Calc for C21H25ClN2O+0.3H2O: C, 69.62; H, 7.12; N, 7.73. Found: C, 69.63; H, 7.34; N, 7.60; ESMS m/e: 357.3 (M+H)+.
4-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]-1-PHENYL-1-BUTANONE: Using Method I, the desired product was obtained. 250 mg; Anal. Calc for C21H26N2O+0.2H2O: C, 77.36; H, 8.16; N, 8.59. Found: C, 77.55; H, 8.12; N, 8.75; ESMS m/e: 323.3 (M+H)+.
4-[4-(3-ANINOPHENYL)-1-PIPERIDINYL]-1-(2,4-DIMETHOXYPHENYL)-1-BUTANONE: Using Method I, the desired product was obtained. 330 mg; Anal. Calc for C23H30N2O3+0.5H2O: C, 70.56; H, 7.98; N, 7.16. Found: C, 70.69; H, 7.87; N, 6.99; ESMS m/e: 383.3 (M+H)+.
METHOD II. General Procedure for the Acylation or Sulfonylation of the Substituted 4-[4-(3-Aminophenyl)-1-piperidinyl]-1-(4-phenyl)-1-butanones: A mixture of 1 equivalent of a substituted 4-[4-(3-aminophenyl)-1-piperidinyl]-1-(4-phenyl)-1-butanone, 1.5 equivalent of an acid chloride or a sulfonyl chloride, and 5 equivalents of diisopropylethylamine, in dichloromethane was stirred at room temperature for two days. The reaction mixture was applied to a preparative TLC plate and eluted with dichloromethane:methanol (15:1, containing 1% isopropyl amine) to give the desired product.
METHOD III. General procedure for the Preparation of the substituted 4-N-(3-{1-[4-(phenyl)-4-oxobutyl]-4-piperidinyl}phenyl)acetamides: A mixture of N-[3-(4-piperidinyl)phenyl]acetamide (1.0 eq) and an aryl substituted chlorobutyrophenone (2.0 eq), K2CO3 (5.0 eq), diisopropylethylamine (3.0 eq) and tetrabutylammonium iodide (cat. 5-10%) in dioxane (0.5 to 1.0 M) were heated at reflux temperature for 16 h. The reaction mixture was filtered and concentrated in vacuo. The crude product was chromatographed using silica preparative TLC (chloroform:methanol containing 0.5% isopropyl amine) to give the desired product.